The broad objective of this revised project is to establish cGMP-activating factors as novel and effective chronic therapeutic strategies to attenuate the development of cardiac fibrosis in hypertensive heart disease (HHD). Here we propose studies of the Natriuretic Peptides (NPs) that target particulate guanylyl cyclase (pGC) and a novel new compound BAY 41-2272 (BAY) that directly targets soluble guanylyl cyclase (sGC) independent of Nitric Oxide (NO). We also propose to define cardioprotective benefits of anti-fibrotic cGMP therapies in HHD that go beyond conventional therapies to enhance myocardial function in addition to improving myocardial structure. Further, we also propose to define new insights into the mechanisms by which the NPs and BAY inhibit cardiac fibroblast (CF) proliferation with a specific focus on molecular mechanisms whereby these cGMP-activating compounds inhibit cellcycle progression. Thus, Project 2 addresses the Central Theme of all projects that is innovative therapeutic strategies for cardiovascular disease. Our Specific Aims and Hypotheses are as follows: Aim 1: Determine the anti-fibrotic and myocardial properties of pGC activation with chronic BNP or CBNP therapy in HHD compared to chronic thiazide diuretic therapy. Hypothesis: Chronic NP therapy will be superior to thiazide diuretic therapy in preventing cardiac fibrosis, suppressing activation of profibrotic factors, improving ventricular function and enhancing myocardial perfusion in HHD. Aim 2: Determine the anti-fibrotic and myocardial properties of chronic sGC activation with chronic BAY therapy in HHD compared to chronic thiazide diuretic therapy. Hypothesis: Chronic BAY therapy will be superior to thiazide diuretic therapy in preventing cardiac fibrosis, suppressing activation of pro-fibrotic factors, improving ventricular function and enhancing myocardial perfusion in HHD. Aim 3: Determine in CFs isolated from normal and HHD hearts the mechanism(s) by which the NPs and BAY inhibit cell cycle progression induced by CT-1 and ET-1. Hypothesis: pGC activation by the NPs or sGC activation by BAY will, via cGMP production, decrease cyclin D1 and E, Rb phosphorylation status, and increase p16 and p21 proteins and thus inhibit entrance into the S-phase of the cell cycle.